Jutta Renkonen

Endothelial and epithelial expression of sialyl Lewisx and sialyl Lewisa in lesions of breast carcinoma

Tumor cells can invade and generate metastasis via either lymphatics or blood vessels. When tumor cells are circulating in the blood, they must adhere to the vessel wall, which is lined by endothelium, before they can extravasate and form new metastases. Several families of adhesion molecules have been identified to play a role in the extravasation cascade. Selectins and their sialyl Lewisx and/or sialyl Lewisa (sLex and sLea, respectively) containing ligands play an initiating role in this cascade; we have now analyzed their role in the generation of metastatic breast carcinoma lesions. We examined expression of endothelial E‐ and P‐selectin, expression of epithelial and endothelial sLex and sLea normal tissues compared with primary and metastatic breast in carcinoma lesions within individual patients. While normal breast epithelial cells do not express sLex or sLea, epithelial expression of these oligosaccharide epitopes was enhanced in primary breast carcinoma lesions. Furthermore, epithelial expression levels of sLex and/or sLea were even higher in most patients (9 of 12) who had metastatic compared with primary lesions. We show that endothelia in primary lesions express more sLex than in normal tissue and that metastatic lesions express even higher amounts of sLex compared with primary lesions. The expression of P‐ and E‐selectin was also greatly enhanced in tumor‐bearing tissue compared with normal tissue. Our data support the hypothesis that while they are circulating in the blood, sLex‐ and/or sLea‐expressing carcinoma cells have a higher probability for extravasation at sites where the endothelium expresses E‐ and P‐selectin and for generation of new metastases. Int. J. Cancer 74:296‐300, 1997.

Expression of cyclo-oxygenase-2 in human tongue carcinoma and its precursor lesions

Abstract. The expression of Cox-2 protein was studied by immunohistochemistry in normal oral mucosa and in mucosa with various lesions of oral leukoplakia, including hyperplasia and dysplasia of squamous epithelium and frank invasive squamous carcinoma. A gradient of Cox-2 staining was found: the expression of Cox-2 was lowest in normal epithelium, somewhat increased in hyperplastic epithelium, further increased in dysplastic epithelium, and highest in invasive squamous cell carcinomas. The presence of Cox-2 in squamous cell carcinomas of the oral mucosa and its precursor lesions indicate that Cox-2 could participate in the carcinogenic process of these oral malignancies.

Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites.

Inflammatory diseases are characterized by the leukocyte infiltration into tissues. L-selectin on lymphocytes and its endothelial glycosylated ligands are instrumental in the initiation of lymphocyte extravasation. Immunohistochemical stainings with monoclonal antibodies against functionally active glycan-decorated L-selectin ligands, ie, sialyl-Lewis x (sLex, 2F3, and HECA-452) or sulfated extended core 1 lactosamine (MECA-79), were performed on more than 400 specimen representatives for thyroiditis, myocarditis, psoriasis, vasculitis, ulcerative colitis, and their corresponding noninflamed tissues. The endothelial expression of sLex or sulfo sLex glycans in postcapillary venules was either absent or low in control tissues. The de novo induction of endothelial expression of sLex or sulfo sLex glycans was detected in all inflamed tissues. Furthermore, each organ carried its own modification of sLex or sulfo sLex glycans, ie, zip code. Our results suggest that these zip code glycans may provide means for organ selective leukocyte traffic that could be used in selective leukocyte traffic inhibition.

In vitro experimental studies of sialyl Lewis x and sialyl Lewis a on endothelial and carcinoma cells: crucial glycans on selectin ligands

Extravasation from the blood of malignant tumour cells that form metastasis and leukocytes that go into tissues require contact between selectins and their sialyl Lewis x and sialyl Lewis a (sLex and sLea respectively) decorated ligands. Endothelial cells have been shown to express sLex epitopes in lymph nodes and at sites of inflammation, and this is crucial for the selectin-dependent leukocyte traffic. Besides the ability to synthesize sLex on sialylated N-acetyllactosamine via the action of α(1,3)fucosyltransferase(s), endothelial cells can also degrade sLex to Lewis x through the action of α(2,3)sialidase(s). In addition, several epithelial tumors possess the machinery to synthesize sLex, which facilitates their adhesion to endothelial E- and P-selectin.

Caveolar transport through nasal epithelium of birch pollen allergen Bet v 1 in allergic patients.

BACKGROUND Previous work in type I pollen allergies has focused on aberrant immunoresponses. OBJECTIVE Our systems-level analyses explore the role of epithelium in early pathogenesis of type I allergic reactions. METHODS We began top-down analyses of differences in human nasal epithelial cells and biopsy specimens obtained from patients with birch allergy and healthy control subjects in the resting state and after intranasal in vivo birch pollen challenges. Immunohistochemistry, immunotransmission electron microscopy, mass spectrometry, transcriptomics, and integration of data to a pathway were conducted. RESULTS Bet v 1 allergen bound to epithelium immediately after in vivo birch pollen challenge during winter only in allergic individuals. It also travelled through epithelium with caveolae to mast cells. Sixteen unique proteins were found to bind to the Bet v 1 column only in lysates from allergic epithelial cells; 6 of these were caveolar and 6 were cytoskeletal proteins. The nasal epithelial transcriptome analysis from allergic and healthy subjects differed during the winter season, and these subjects also responded differentially to birch pollen challenge. Within this pollen-induced response, the gene ontology categories of cytoskeleton and actin cytoskeleton were decreased in allergic patients, whereas the actin-binding category was enriched in healthy subjects. Integration of microscopic, mass spectrometric, and transcriptomic data to a common protein-protein binding network showed how these were connected to each other. CONCLUSION We propose a hypothesis of caveolae-dependent uptake and transport of birch pollen allergen in the epithelium of allergic patients only. Application of discovery-driven methodologies can provide new hypotheses worth further analysis of complex multifactorial diseases, such as type I allergy.

Allergy as an epithelial barrier disease.

The objective of this review is to focus on putative modified epithelial functions related to allergy. The dysregulation of the epithelial barrier might result in the allergen uptake, which could be the primary defect in the pathogenesis of allergic reaction. We review the literature of the role of respiratory epithelium as an active barrier, how allergens are transported through it and how it senses the hostile environmental allergens and other dangerous stimuli.

Time-series nasal epithelial transcriptomics during natural pollen exposure in healthy subjects and allergic patients.

To cite this article: Mattila P, Renkonen J, Toppila‐Salmi S, Parviainen V, Joenväärä S, Alff‐Tuomala S, Nicorici D, Renkonen R. Time‐series nasal epithelial transcriptomics during natural pollen exposure in healthy subjects and allergic patients. Allergy 2010; 65: 175–183.

Endothelial L-selectin ligand expression in nasal polyps

Background:  L‐selectins on leukocytes and their counter‐receptors on endothelial cells have been shown to be involved in leukocyte recruitment in chronic rhinosinusitis without nasal polyps (NP).

Birch pollen allergen Bet v 1 binds to and is transported through conjunctival epithelium in allergic patients.

Background:  Previous work in type‐I pollen allergies has mainly focused on lymphocytes and immune responses. Here, we begin to analyse with a systems biology view the differences in conjunctival epithelium obtained from healthy and allergic subjects.

Molecular Mechanisms of Nasal Epithelium in Rhinitis and Rhinosinusitis

Allergic rhinitis, nonallergic rhinitis, and chronic rhinosinusitis are multifactorial upper airway diseases with high prevalence. Several genetic and environmental factors are proposed to predispose to the pathogenesis of the inflammatory upper airway diseases. Still, the molecular mechanisms leading toward the onset and progression of upper airway diseases are largely unknown. The upper airway epithelium has an important role in sensing the environment and regulating the inhaled air. As such, it links environmental insults to the host immunity. Human sinonasal epithelium serves as an excellent target for observing induced early-phase events, in vivo, and with a systems biological perspective. Actually, increasing number of investigations have provided evidence that altered homeostasis in the sinonasal epithelium might be important in the chronic upper airway inflammation.